A listing of human cancers for which chemotherapy has exerted a predominant role in increasing life span, approaching normal life expectancy, includes Burkitt""s lymphoma, acute lymphocytic leukemia and Hodgkin""s disease, along with about 10-15 other tumor types. For example, see A. Golden et al., Eur. J. Cancer, 17, 129 (1981) (Table 1). While the cure rate of these cancers illustrates the level of success of screening systems in selecting antitumor agents that are effective in man, these responsive tumors represent only a small fraction of the various types of cancer and, notably, there are relatively few drugs highly active against clinical solid tumors. Such drugs include cyclophosphamide, adriamycin, 5-FU, hexamethylmelamine and the like. Thus, patients with many types of malignancies remain at significant risk for relapse and mortality.
After relapse, some patients can be reinduced into remission with their initial treatment regimen. However, higher doses of the initial chemotherapeutic agent or the use of additional agents are frequently required, indicating the development of at least partial drug resistance. Recent evidence indicates drug resistance can develop simultaneously to several agents, including ones to which the patient was not exposed. The development of multiple-drug resistant (mdr) tumors may be a function of tumor mass and constitutes a major cause of treatment failure. To overcome this drug resistance, high-dose chemotherapy with or without radiation and allogenic or autologous bone marrow transplantation can be employed. The high-dose chemotherapy may employ the original drug(s) or be altered to include additional agents. The development of new drugs non-cross resistant with mdr phenotypes is required to further the curative potential of current regimens and to facilitate curative interventions in previously treated patients.
Recently, the in vitro anti-tumor activity of a novel class of natural products called illudins was examined by Kelner, M. et al., Cancer Res., 47, 3186 (1987), incorporated herein by reference. Illudin M was purified and submitted for evaluation to the National Cancer Institute Division of Cancer Treatment (NCI DCT) in vivo drug screening program. Illudin M significantly increased the life span of rats with Dunning leukemia, but had a low therapeutic index in solid tumor systems. The extreme toxicity of illudins has prevented any applications in human tumor therapy. Recently, synthetic analogs of the illudins have been developed which exhibit promising antitumor activity, including U.S. Pat. Nos. 5,439,936 and 5,523490.
However, there exists a continuing need for chemotherapeutic agents which inhibit tumor growth, especially solid tumor growth, and which have an adequate therapeutic index to be effective for in vivo treatment.
The present invention provides illudin analogs of the general formula (I): 
wherein R1 is (CH2)nxe2x80x94(X)xe2x80x94(Y) or H; n is 0-4, X is O or S or N, and Y is CH2OC(O) (C1-C4)alkyl, (C1-C8)alkyl optionally substituted with 1-2 OH or 1-2 halo (Cl, Br, I or F); a saccharide, preferably a monosaccharide, preferably fructose; CH2C(O)xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94C(O)CH2SH, (CH2)2xe2x80x94Oxe2x80x94(CH2)2W wherein W is halo; (C1-C8)alkylxe2x80x94Oxe2x80x94(C1-C8)alkyl; (C6-C10)aryl, (C6-C10)aryl(C1-C4)alkyl or C(O)O(C6-C10)aryl, wherein the aryl moiety is optionally substituted with 1-2 OH, halo, (C1-C4)alkyl or O(C1-C4)alkyl; CH2CO2(C1-C4)alkyl, CH2CO2H, Si((C1-C4)alkyl)3, an amino acid residue, preferably alanyl; or H with the proviso that when Y is H, n is 2-4; or
X is absent, and Y is CHO, NO2, COOH, OAc, (C2-C4)alkenyl-CHO, CH(O(C1-C4)alkyl)2; cyclo(C3-C6)alkyl or (C5-C12)aryl optionally comprising 1-3 heteroatoms selected from N, S, or non-peroxide O, optionally substituted with 1-2 (C1-C4)alkyl, CHO, OH or halo;
R2 is absent; or R1xe2x80x94Cxe2x80x94Cxe2x80x94R2 together comprise a 5-7 membered ring, optionally comprising one or more, preferably 1-2, heteroatoms selected from N, S, or non-peroxide O, and optionally substituted with (C1-C4)alkyl, OH or halo;
R3 is H or (C1-C4)alkyl;
R4 is H, SCH2CO2(C1-C4)alkyl, Oxe2x80x94(C5-C12)aryl or Sxe2x80x94(C5-C12)aryl where aryl is optionally substituted with halo, OH or (C1-C4)alkyl;
R5 is H, OH or absent;
R6 is (C1-C4)alkyl or H; and
R7 is OH or Si((C1-C4)alkyl)3; or
R6 and R7 together are ethylenedioxy;
R8 is (C1-C4)alkyl, optionally substituted with OH or halo;
the bonds represented byxe2x80x94are present or absent; and
the pharmaceutically acceptable salts thereof.
Preferably when X is absent, n is 2 to 4.
The present invention also provides compounds of formula (I) wherein the cyclopropyl group is replaced with xe2x80x94(CH2)2OH, and the carbonyl oxygen is replaced with a hydroxyl group, yielding compounds of the formula (II) 
where R1-R4 are defined as in Formula (I), and the bonds represented byxe2x80x94are individually present or absent. Preferably, however, R1 is (C1-C4)alkyl-Z where Z is OH or halo, or xe2x80x94Sxe2x80x94(C5-C12)aryl, preferably xe2x80x94S-phenyl, and the aryl group is optionally substituted with 1-2 OH, halo or (C1-C4)alkyl; R2 is absent; R3 is (C1-C4)alkyl, preferably Me; and R4 is xe2x80x94Sxe2x80x94(CH2)nxe2x80x94COOH where n is 1-4 or R4 is xe2x80x94S-aryl, preferably xe2x80x94S-phenyl, and the aryl group is optionally substituted with 1-2 OH, -halo or (C1-C4)alkyl.
The invention also provides dimeric compounds comprising compounds of formula (I), wherein the monomeric illudin analogs are the same or different. For example, in formula (I) R1 and R4 can be a compound of formula (I) wherein X and Y are absent. Thus, the invention also provides dimeric compounds comprising compounds of formula (I) wherein the structure of the monomeric compounds is the same or different. Typically, the dimers are of the formula (III) 
where L is a linker group. L may be, by way of example, an alkyl or ester based linker group. Examples of suitable linker groups include xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94(CH2)nxe2x80x94 where n is 1 to 8, and xe2x80x94CH2xe2x80x94Sxe2x80x94CH2C(O)xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94C(O)CH2xe2x80x94Sxe2x80x94CH2xe2x80x94. Other linker groups would be apparent to one skilled in the art. Although shown linked via the 5-position carbons of each analog, it is understood that the analogs may be linked via other positions, such as any combination of the 3-, 5- or 7-position carbon atoms. Where linkage is via a position other than the 5-position, the substituent R1 will be present, and as defined for Formula (I). Where linkage is via the 3-position, it is understood that the cyclopropyl moiety will not be present. Where linkage is via the 5-position carbon of each analog, L is preferably xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Sxe2x80x94CH2C(O)xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94C(O)CH2xe2x80x94Sxe2x80x94CH2xe2x80x94.
These compounds are useful as antineoplastic agents, i.e., to inhibit tumor cell growth in vitro or in vivo, in mammalian hosts, such as humans or domestic animals, and are particularly effective against solid tumors and multi-drug resistant tumors.
Thus, the present invention provides a therapeutic method to treat cancer, i.e., to inhibit tumor cell growth in vitro, or preferably, in AYE, by administration to a mammal, such as a human cancer patient, of an amount of a compound of formula I effective to inhibit the growth of said cancer cells, i.e., tumor cells. The present compounds may be particularly useful for the treatment of solid tumors for which relatively few treatments are available. Such tumors include epidermoid and myeloid tumors, acute (AML) or chronic (CML), as well as lung, ovarian, breast and colon carcinoma. The present compounds can also be used against endometrial tumors, bladder cancer, pancreatic cancer, lymphoma, Hodgkin""s disease, prostate cancer, sarcomas and testicular cancer as well as against tumors of the central nervous system, such as brain tumors, neuroblastomas and hematopoietic cell cancers such as B-cell leukemia/lymphomas, myelomas, T-cell leukemiallymphomas, and small cell leukemia/lymphomas. These leukemia/lymphomas could be either acute (ALL) or chronic (CLL).
The present compounds may also be targeted to a particular tumor by attaching the compound to a reagent which is capable of binding to a tumor-associated antigen. The antigen may be located on a tumor or in the tumor cell area. Suitable reagents include polyclonal and monoclonal antibodies. The compound-reagent complex may further comprise a linker for attaching the compound to the reagent.
The present invention also provides pharmaceutical compositions, such as pharmaceutical unit dosage forms, comprising an effective anti-neoplastic amount of one or more of the present illudin analogs in combination with a pharmaceutically acceptable carrier.
As used herein, with respect to the present method, the term xe2x80x9cinhibitxe2x80x9d means either decreasing the tumor cell growth rate from the rate which would occur without treatment, or causing the tumor cell mass to decrease in size. Inhibiting also includes causing a complete regression of the tumor. Thus, the present analogs can either be cytostatic or cytotoxic to the tumor cells.
The subject can be any mammal having a susceptible cancer, i.e., a malignant cell population or tumor. The analogs are effective on human tumors in v as well as on human tumor cell lines in vitro.